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Abstract

Introduction

Intensive insulin therapy (IIT) with tight glycemic control may reduce mortality and
morbidity in critically ill patients and has been widely adopted in practice throughout
the world. However, there is only one randomized controlled trial showing unequivocal
benefit to this approach and that study population was dominated by post-cardiac surgery
patients. We aimed to determine the association between IIT and mortality in a mixed
population of critically ill patients.

Methods

We conducted a cohort study comparing three consecutive time periods before and after
IIT protocol implementation in a Level 1 trauma center: period I (no protocol); period
II, target glucose 80 to 130 mg/dL; and period III, target glucose 80 to 110 mg/dL.
Subjects were 10,456 patients admitted to intensive care units (ICUs) between 1 March
2001 and 28 February 2005. The main study endpoints were ICU and hospital mortality,
Sequential Organ Failure Assessment score, and occurrence of hypoglycemia. Multivariable
regression analysis was used to evaluate mortality and organ dysfunction during periods
II and III relative to period I.

Results

Insulin administration increased over time (9% period I, 25% period II, and 42% period
III). Nonetheless, patients in period III had a tendency toward higher adjusted hospital
mortality (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.98, 1.35) than patients
in period I. Excess hospital mortality in period III was present primarily in patients
with an ICU length of stay of 3 days or less (OR 1.47, 95% CI 1.11, 1.93 There was
an approximately fourfold increase in the incidence of hypoglycemia from periods I
to III.

Conclusion

A policy of IIT in a group of ICUs from a single institution was not associated with
a decrease in hospital mortality. These results, combined with the findings from several
recent randomized trials, suggest that further study is needed prior to widespread
implementation of IIT in critically ill patients.

Introduction

Stress-induced hyperglycemia occurs frequently in critically ill patients and has
been associated with increased morbidity and mortality in both diabetic and non-diabetic
patients and in patients with traumatic injury [1-3], stroke [4-7], anoxic brain injury [8], acute myocardial infarction [9], post-cardiac surgery [10], and other causes of critical illness [11-13]. If causal, the mechanisms by which hyperglycemia affects outcomes could be related
to suppressive effects on immune function and an associated increased risk of infection
[14-16], endothelial damage [17], hepatocyte mitochondrial damage [18], and potentiation of tissue ischemia due to acidosis or inflammation [19,20].

Two observational [21,22] and two randomized [23,24] trials of surgical and medical critically ill patients have observed a higher incidence
of favorable outcomes in critically ill patients treated with intensive insulin therapy
(IIT) to achieve a blood glucose level of 80 to 110 mg/dL. However, other recently
published studies suggest that there may be no benefit or even harm conferred by this
approach in patients during cardiac surgery or recovering from cardiac arrest [25,26]. In addition, two recent randomized trials of IIT in critically ill patients were
stopped early due to lack of benefit and hypoglycemia associated with IIT [27].

Although there is still debate whether the evidence is adequate to support a clear
recommendation, the Institute for Healthcare Improvement [28] is recommending a care 'bundle' for severe sepsis which includes intensive glycemic
control. Likewise, the Volunteer Hospital Association [29] uses glucose control as a quality indicator. As a result of these recommendations
(which were made prior to the availability of the results from the most recent studies),
tight glycemic control has increasingly become the standard of care for critically
ill patients at our institution.

The objective of the present study was to investigate the effect of implementing a
policy of tight glycemic control in a broader population of critically ill patients
than previously studied, including a mix of trauma, surgical, neurosurgical, and medical
intensive care unit (ICU) patients. To this end, we examined the outcomes of all patients
admitted to the ICUs at Harborview Medical Center, a Level I trauma center and county
hospital in Seattle, WA, before and after the introduction of intensive insulin protocols.

Materials and methods

Source population

Harborview Medical Center is a 374-bed municipal medical center affiliated with the
University of Washington, Seattle, WA, and the only Level 1 trauma center in a five-state
area (Washington, Wyoming, Alaska, Montana, and Idaho). There are seven ICUs located
at Harborview Medical Center, serving a variety of patients with medical and surgical
illness. The majority of patients are covered by ICU services with intensive staffing
models, and all critical care protocols are implemented throughout all ICUs simultaneously.
Nursing staffing ratios remained constant throughout the study period. For the purpose
of this study, a cohort of all patients admitted to these ICUs over the course of
a 4-year period between 1 March 2001 and 28 February 2005 was selected. All data were
available from the hospital database originating from computerized medical and billing
records and from a prospectively collected registry of trauma-related admissions [30]. The study was approved by the University of Washington Institutional Review Board,
which waived the need for informed consent.

Study design

The cohort was divided into three periods corresponding to changing glycemic control
goals and insulin therapy protocols: period I, 1 March 2001 to 28 February 2002; during
this period, there was no specific glycemic control protocol, and hyperglycemia was
treated by a mix of subcutaneous and intravenous insulin, with a general target blood
glucose of 120 to 180 mg/dL; period II, 1 March 2002 to 30 June 2003 (target blood
glucose of 80 to 130 mg/dL); and period III, 1 July 2003 to 28 February 2005 (80 to
110 mg/dL). Study period was considered as a surrogate of IIT and was used as the
main predictor of interest. The intensive insulin protocols consisted of explicit
target glucose ranges and of dosing orders for intravenous insulin by continuous infusion
combined with intravenous boluses if necessary (Appendix 1). In addition, educational
efforts were directed at physicians and nursing staff to emphasize the potential benefits
of tight glycemic control and to alert practitioners to the protocols. There were
no major changes in glycemic management on the acute care wards during the study periods.
Three other critical care protocols designed to improve clinical outcomes were implemented
at the study hospital in 2001–2003: (a) a procedure for invasive diagnosis of ventilator-associated
pneumonia (fall of 2001), (b) a lung protective ventilation protocol (spring of 2002),
and (c) a protocol for liberation from mechanical ventilation (spring of 2003). There
were no changes in the indications for admission to the ICU during the study period.

For each patient, only the first ICU stay per hospitalization and the first hospital
stay were included in this analysis. Patients were excluded if their ICU stay was
shorter than 24 hours or if the ICU stay was not completed before the end of the study
period during which they were admitted. Patients younger than 16 years of age were
also excluded.

Blood glucose levels obtained closest in time to 6 a.m. were collected from the central
laboratory analyzer. This convention was chosen based on reporting of glycemic control
in the two large randomized trials of IIT in critically ill patients and to provide
consistency in reporting given the potential inaccuracy of capillary point-of-care
glucose measurements in critically ill patients [23,24,31]. For frequency of hypoglycemia, data were included from both central laboratory measurements
and point-of-care glucose testing in order to capture all hypoglycemic events.

Patients were classified by the admitting ICU service (surgical, medical, coronary,
neurosurgical, or burn) and by the type of admission (surgical versus medical). The
latter was determined by which service the majority of time in the ICU was spent after
admission. Surgical admissions include those patients who spent the majority of their
ICU time on the surgical, neurosurgical, or burn ICU services. In addition, the proportion
of patients admitted after trauma was determined.

Statistical analysis

Primary outcome measures defined a priori included ICU and hospital mortality. Secondary safety outcome measures included occurrence
of moderate (glucose of less than 65 mg/dL) and severe (glucose of less than 40 mg/dL)
hypoglycemia at any time during the ICU stay. Additional a priori-specified secondary outcomes included evidence of organ dysfunction as measured by
Sequential Organ Failure Assessment (SOFA) scores.

Confounders were selected on the basis of a priori knowledge to account for severity of disease and other risk factors. Severity of illness
was measured by the Simplified Acute Physiology Score (SAPS) II and the Acute Physiologic
Score (APS) of the APACHE (Acute Physiology and Chronic Health Evaluation) III score
in the first 24 hours of ICU admission in all patients; these scores were calculated
from information available in the electronic medical record. The Injury Severity Score
was obtained in all patients admitted after traumatic injury from the Harborview Trauma
Registry. Other potential confounders that were adjusted for included age, race, gender,
comorbidities as defined by SAPS II, mechanical ventilation at ICU admission, and
history of diabetes.

We evaluated the distribution of baseline characteristics and their association with
the mortality among patients admitted to the ICU during each respective insulin protocol
implementation period (study period), using one-way analysis of variance or frequency
tables, as appropriate. As relative risks closely approximated odds ratios (ORs),
results are presented as ORs. All P values are two-sided. Logistic regression was used to model mortality probabilities
in patients admitted in each study period and to adjust for a priori-selected potential confounding factors. Simple logistic regression models that included
the main predictor of interest (study period as a surrogate of IIT) were fitted initially.
Period I was used as a reference prior to the implementation of insulin protocols.
Adjusted models included the main predictor of interest, the a priori-specified confounders, significant predictors of mortality, and additional confounders.

To explore the suggestion that different populations may derive a variable degree
of benefit from insulin therapy, sensitivity analyses were conducted with varying
assumptions regarding the underlying study population, including subgroup analyses
for patients who were in the ICU for 3 days or less or more than 3 days, and further
restricting the analyses to surgical or medical populations and to patients who were
admitted after trauma.

Organ dysfunction scores, as measured by SOFA scores, arise from a mixture of discrete
and continuous processes, making them ill-suited for standard statistical methods
of analysis (for example, linear regression). We analyzed the SOFA scores using a
generalization of the limited dependent variable model developed by Tobin [32] called the tobit model. The tobit model simultaneously combines a probit regression
for the discrete component of the outcome (for example, zero SOFA scores) and a normal
error regression model for the continuous component of the outcome (for example, SOFA
scores greater than zero). For a detailed exposition of the tobit model and some of
its extension, see Amemiya [33]. As SOFA scores are highly skewed, we log-transformed SOFA scores greater than zero
to make the data more normal. We computed robust standard error estimates of the tobit
model's regression coefficients using the non-parametric bootstrap of Efron [34]. Hypothesis tests to investigate associations between predictor variables and SOFA
scores were performed using Wald statistics. STATA statistical software (version 9.2;
StataCorp LP, College Station, TX, USA) was used for all analyses. P values are two-sided.

Results

Study population and baseline characteristics

The study population consisted of 10,456 patients, of whom 2,366 were admitted during
period I, 3,322 during period II, and 4,768 during period III. The number of trauma
patients in the study cohort was 857 (36%) in period I, 1,203 (36%) in period II,
and 1,920 (40%) in period III. The distributions of demographic and baseline characteristics
of the patient population were broadly similar across the three periods (Table 1). Compared with patients admitted during period I, history of type I diabetes was
less frequent in patients admitted in periods II and III, whereas type II diabetes
was more common in the latter periods (Table 1). Blood glucose at ICU admission was lower in period III compared with the other
two periods. The average SAPS II and APS III scores were lower in period III than
in periods I and II. Requirement for mechanical ventilation at ICU admission was less
frequent over time.

Except for gender, ethnic group, history of diabetes I or II, and weight, all variables
in Table 1 were associated with hospital mortality. In particular, the OR of hospital mortality
for admission glucose was 1.0009 (95% confidence interval [CI] 1.0002, 1.0016; P = 0.014) for a 1 mg/dL increase in admission blood glucose.

Insulin use, glucose control, and hypoglycemia

The proportion of patients receiving insulin infusion increased dramatically over
the study periods, from 9% in period I to 25% in period II and then further to 43%
in period III (Table 2). Due to the lower threshold to initiate insulin treatment, and the broadened exposure
to insulin among patients without insulin resistance, patients (on average) received
lower doses of insulin to control blood glucose in period III compared with the previous
two periods. The average 6 a.m. blood glucose concentrations as measured in the central
laboratory decreased from 144 mg/dL in period I to 139 mg/dL in period II to 129 mg/dL
in period III. Moderate (<65 mg/dL) and severe (<40 mg/dL) hypoglycemic events increased
approximately threefold to fourfold from the first to the third study periods (Table
2). There was excess mortality associated with hypoglycemia across the three time periods
(Table 3). We explored the association between mean glucose and mortality restricting the
analysis to period I (baseline). The OR of hospital mortality for mean blood glucose
in period 1 was 1.0078 (95% CI 1.0043, 1.0112; P <0.01).

Mortality

Overall, the crude hospital mortality rates were 14.1% in period I, 15.7% in period
II, and 14.4% in period III (Table 3). These figures are within the range predicted by severity of illness scores (SAPS
II and APS III). After adjusting for age at admission, history of diabetes, SAPS II
with age points removed, admitting service, and mechanical ventilation at ICU admission,
the adjusted relative odds of hospital mortality were not significantly different
for patients who were admitted during period II (OR 1.11, 95% CI 0.93, 1.31) or period
III (OR 1.15, 95% CI 0.98, 1.32) compared with patients who were admitted during period
I (Table 4). In a model that included admission blood glucose levels, the ORs of hospital mortality
were 1.11 (95% CI 0.93, 1.31) in period II and 1.16 (95% CI 0.99, 1.37) in period
III.

Table 3. Crude estimates of mortality, length of stay, and organ dysfunction stratified by
study period

When the models were re-fitted to analyze mortality with categories of ICU length
of stay (LOS), the ORs of hospital mortality were significantly higher in patients
with an ICU LOS of 3 days or less (Table 4). In contrast, in patients with an ICU LOS of greater than 3 days, there was no association
between study period and mortality (Table 4). Hospital mortality was not decreased during period III in either the medical or
surgical population (whether trauma patients or others) (Table 5).

Overall, the crude ICU mortality rates were 9.0% in period I, 10.8% in period II,
and 9.8% in period III. After adjustment, the ORs of ICU mortality were significantly
higher comparing period III (OR 1.26, 95% CI 1.04, 1.53) with period I both in the
entire population (Table 4) and in the subgroups of surgical and trauma patients (Table 5), but not in the medical population.

Organ Dysfunction Score

Overall, the unadjusted mean SOFA score tended to decrease over time across the study
periods (Table 3). However, after adjustment for imbalances in baseline characteristics, including
age, history of diabetes, SAPS II with age points removed, admission blood glucose,
and mechanical ventilation at ICU admission, there was a 0.028 (95% CI -0.004, 0.06;
P = 0.082) increase in the mean of the natural logarithm SOFA score comparing patients
in periods II and I and there was a 0.043 (95% CI 0.013, 0.073; P = 0.005) increase in the mean of the log SOFA score comparing patients in periods
III and I.

Discussion

The present study observed that implementation of IIT, with the percentage of patients
receiving insulin by infusion increasing from 9% in period I to 42% in period III,
was associated with no hospital mortality benefit. Furthermore, an incremental mortality
increase associated with IIT was observed in patients with an ICU stay of 3 days or
less. These latter findings are consistent with those from a similar subgroup in a
randomized controlled trial (RCT) of IIT in medical ICU patients [24].

Our study has several potential limitations. Despite our effort to control for confounding
by assessing patient characteristics across the three study periods and adjusting
for any baseline differences seen, the possibility of bias remains. However, arguing
in support of a true incremental mortality associated with tighter glucose control
was that the trend observed was opposite of what might have been expected if confounding
had been present, given that several other clinical protocols designed to improve
patient outcomes were implemented in the ICUs of the study hospital at around the
same time as the IIT protocols. Admittedly, two of these protocols would not be expected
to have any appreciable effect on mortality (invasive diagnosis of ventilator-associated
pneumonia and ventilator weaning protocol) and the third (a protocol for lung protective
ventilation) was widely practiced prior to formal protocol release. We did not observe
any mortality differences between the first and second halves of each study period,
arguing against an overall trend of increasing in mortality during the study (data
not shown). These arguments suggest that our approach to evaluating the impact of
the implementation of an IIT protocol on mortality is a valid one.

The major strength of the current study lies in the large cohort of patients included
(>10,000) and the availability of extensive clinical data that allowed adjustment
for severity of illness across time periods.

Four prior published studies have observed at least some reduction in mortality associated
with IIT in critically ill patients. Van den Berghe and colleagues [23] reported the results of a large randomized trial of IIT in patients admitted to a
surgical ICU, approximately 60% of whom had undergone cardiac surgery. IIT (blood
glucose range of 80 to 110 mg/dL) was associated with a reduction in mortality from
8.0% to 4.6% compared with conventionally treated patients (blood glucose range of
180 to 200 mg/dL) in addition to reductions in multiple morbidities [23]. In a subsequent study, van den Berghe and colleagues [24] randomly assigned patients admitted to a medical ICU to IIT or conventional blood
glucose management. There was no clear mortality benefit for IIT in the intention-to-treat
population, whether for ICU (24.2% IIT group versus 26.8% conventional treatment group)
or hospital (37.3% IIT versus 40% conventional treatment group) mortality. However,
IIT was associated with reduced in-hospital mortality in those patients who remained
in the ICU for more than 3 days. In two studies that reported outcomes before and
after implementation of an intensive glucose management protocol, mortality after
implementation of the protocol was improved compared with prior to protocol implementation
[21,22]. However, neither study adjusted for severity of illness or other factors that may
have changed over time.

There are several reasons that may explain why the results of our study differ from
these previous investigations of IIT. The implementation of progressively more aggressive
insulin therapy protocols at our institution resulted in a large change in practice:
the use of IIT rose from 9.6% of patients in period I to 42% in period III. Although
this resulted in a reduction in mean daily and mean morning glucose concentrations,
with a difference of approximately 15 mg/dL between periods I and III, we were unable
to consistently achieve blood glucose concentrations within the range of 80 to 110
mg/dL. It is possible that the benefits of IIT are not achieved unless glucose concentrations
are lower than 110 mg/dL.

Failure to achieve the targeted glucose levels reflects the difficulty in application
of clinical protocols to real-world practice, outside the rigid confines of RCTs,
and has been recognized previously [35-37]. Despite an explicit protocol combined with continuing educational efforts to alert
physicians and nurses to the potential benefits of tight glycemic control, glucose
levels (on average) remained approximately 20 mg/dL above the target range. This 'failure'
likely occurred at several levels, although we are unable to discern specific causes
within the limitations of our study design.

A major difference between our cohort and that included in the trials of van den Berghe
and colleagues [23,24] is the form of nutritional support used. In the studies of van den Berghe and colleagues,
nutritional support was very aggressive: parenteral nutrition was administered early
in the course of care and comprised the vast majority of non-protein calories during
the first few days of ICU stay. This is in contrast to the practice at our institution,
where parenteral nutrition generally is not instituted until 3 to 5 days after ICU
admission. Parenteral nutrition reduces endogenous glucose production and promotes
hyperglycemia in critical illness, effects which may be modulated by insulin administration
[38]. It is not clear how these effects would translate into increased benefit from IIT.

Finally, our study differs from the trials of van den Berghe and colleagues [23,24] in that we examined a mixed population of critically ill patients, with approximately
60% of patients carrying a surgical diagnosis at admission, with a high representation
of trauma patients (approximately 56% of the entire study cohort), including those
with neurological injury. Our data suggest that, if anything, ITT was associated with
an increased mortality among trauma patients, although the reasons for this are not
clear. Previous retrospective studies have found an association between hyperglycemia
and mortality in trauma patients [1,2,39-43] and possibly a lower mortality temporally associated with the implementation of an
IIT protocol and reduction in glucose variability [22,44]. However, our study is the first to examine the effects of IIT on outcome in this
population, applying rigorous adjustments for patients' baseline characteristics.
Cardiac surgical services are not performed at out institution; therefore, our surgical
population differs from that of the study of van den Berghe [23], in which the majority of patients were recovering from cardiovascular surgery.

Several other studies also did not observe evidence of benefit of ITT. A recently
published multicenter RCT in 537 patients with severe sepsis found no difference in
mortality or organ failure in IIT versus conventional glucose management groups [45]. The incidence of severe hypoglycemia was increased in patients randomly assigned
to IIT (17.0% versus 4.1%). Another recent study investigated the effect of intraoperative
IIT on the outcome of patients undergoing cardiac surgery [46]. Patients were randomly assigned to IIT (glucose range of 80 to 100 mg/dL) or conventional
treatment (glucose of less than 200 mg/dL). The study reported higher mortality and
higher occurrence of strokes in the IIT group. A third recent RCT found no mortality
benefit and a much higher incidence of hypoglycemia in a group of patients treated
to maintain glucose less than 108 mg/dL for 48 hours after cardiac arrest compared
with a group treated to maintain glucose less than 144 mg/dL [26]. A prospective consecutive series of 818 patients admitted to a trauma ICU found
no reduction in mortality or infectious complications in association with the implementation
of a normoglycemic management protocol (glucose goal of 80 to 110 mg/dL) [47]. Additionally, preliminary results from another recently completed randomized trial
of IIT in ICU patients showed no significant mortality difference and an increase
in the risk of hypoglycemia [27,48].

The reason that IIT may result in increased mortality is unclear but may be related
to a direct effect of insulin or to insulin-induced hypoglycemia. Two previous studies
have found an association between ICU mortality and insulin administration [49,50]; the mechanism by which insulin may confer harm is not clear but might be related
to anabolic effects, similar to growth hormone [51-53]. Two studies have examined the association between hypoglycemia and mortality in
critically ill patients using case control methodology, with one finding no effect
[54] and the other suggesting an independent association between severe hypoglycemia and
mortality [55]. Further exploration of these areas is warranted.

It is unclear why we found increases in ICU mortality in the entire cohort and in
some subgroups whereas there were only trends toward increased hospital mortality
(Tables 4 and 5). For hospital mortality, the signal in the data could be attenuated due to the underlying
noise of hospital deaths not related to glycemic control. It is also possible that
ICU mortality reflects more glycemic control-related deaths than deaths from all causes.
The association between period and ICU or hospital mortality was stronger in patients
with a short ICU stay. This finding was also observed in the second randomized trial
of van den Berghe and colleagues [24]. It is also possible, though speculative, that IIT confers some longer-term survival
benefit that offsets adverse effects seen during the ICU stay.

Conclusion

We observed that IIT in a mixed cohort of critically ill patients was not associated
with a reduction in hospital mortality, and was associated with increased ICU and
hospital mortality in some subgroups. These results, combined with data from the most
recently concluded randomized trials, suggest that broad implementation of IIT may
be premature and that additional randomized trials in diverse groups of critically
ill patients are necessary.

Key messages

• In a mixed population of critically ill patients, a large proportion of whom had
suffered traumatic injury, intensive insulin therapy (IIT) was not associated with
a reduction in adjusted hospital mortality.

• IIT was associated with an increase in intensive care unit (ICU) mortality and risk
of organ failure after adjustment for baseline characteristics.

• The increase in adjusted ICU mortality was largest for the subgroup of patients
admitted after trauma.

• Hospital and ICU mortality were increased in the subgroup of patients with an ICU
length of stay of less than 3 days.

• The incidence of severe hypoglycemia increased approximately fourfold after implementation
of IIT, although the incidence remained much lower than that reported in randomized
trials of IIT.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MMT, VK, NDY, NW, and SAD were involved in the concept and design of the study, the
analysis and interpretation of data, drafting the article or revising it critically
for important intellectual content, and final approval of the version to be published.
SD was involved in the concept and design of the study and in the analysis and interpretation
of data. All authors read and approved the final manuscript.

Appendix 1

Intensive insulin protocol used during period II of the study. These orders were modified
slightly for use during period III in order to achieve a glucose goal closer to 81
to 110 mg/dL.

Acknowledgements

This study was supported, in part, by an unrestricted grant from Roche Diagnostics
Corporation (Indianapolis, IN, USA). The funding source had no involvement in study
design; collection, analysis, and interpretation of data; in the writing of the report;
or in the decision to submit the article for publication. Ethical approval for this
study was provided by the University of Washington Human Subjects Division.